Numerous reports have documented a marked increased incidence of disordered mineral and bone metabolism in patients receiving chronic anticonvulsant drug therapy. Our previous studies have demonstrated (1) significantly reduced serum calcium and 5-hydroxyvitamin D (25-OHD) levels, and osteopenia in anticonvulsant drug-treated patients (2) evidence for direct drug effects on vitamin D metabolism and bone homeostasis. The proposed studies will intensively investigate the nature of these processes. Refinements of current receptor and high pressure liquid chromatographic (HPLC) assays for vitamin D metabolites, combined with turnover studies of stable and radiolabelled vitamin D metabolites, will allow direct quantitation of drug-induced disorders of vitamin D metabolism. Abnormal drug-induced vitamin D metabolites will be characterized by standard chromatographic, HPLC, bioassay and mass spectrographic techniques. Studies of direct drug effects on in vivo vitamin D metabolite binding, uptake and metabolism in liver and kidney will further define both the normal metabolic pathways and drug-induced abnormalites in vitamin D metabolite processing. Chronic animal studies will determine the sequence of events involved in drug induction disorders of serum mineral homeostasis, intestinal calcium transport, target-organ localization of vitamin D metabolites and bone kinetic parameters. In vitro bone culture systems will be employed to assess normal and drug-altered processes of ion transport, cyclic nucleotide generation amino acid uptake, collagen synthesis and resorption. Studies of drug effects on mineral and 25-OHD metabolism in isolated renal mitochondria will assess possible abnormalities in control mechanisms for vitamin D activation. Finally, studies of drug effects on in vitro hepatic vitamin D metabolism will further define the role of microsomal enzyme induction in this disorder.